Chest
Volume 141, Issue 2, Supplement, February 2012, Pages e152S-e184S
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Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles
Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

https://doi.org/10.1378/chest.11-2295Get rights and content

Background

High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.

Methods

The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.

Results

Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.

Conclusions

We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Section snippets

Summary of Recommendations

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.1. For patients sufficiently healthy to be treated as outpatients, we suggest initiating vitamin K

Methods

The methods for the development of this article's recommendations follow those developed for the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.2 Although we aimed to summarize and use randomized controlled trial (RCT) evidence to inform recommendations for clinicians, we found only lower-quality evidence to address most of our questions. At the onset of our review process, our panel decided to limit

Initial Dose Selection—Loading Dose

Loading doses of VKA may be worth considering where rapid attainment of therapeutic international normalized ratio (INR) is required and considered safe, primarily for patients with VTE. Predictable and timely achievement of therapeutic INRs without increased risk of bleeding or recurrent thromboembolic events avoids the inconvenience and pain of prolonged administration of subcutaneous (SC) low-molecular-weight heparin (LMWH) and facilitates early patient discharge and eligibility for

Monitoring Frequency for VKAs

The frequency of long-term INR monitoring is influenced by patient compliance, changes in health status, the addition or discontinuation of interacting medications, changes in diet, the quality of dose-adjustment decisions, and whether the patient has demonstrated stable INRs.23, 24, 25 We define stable INRs as at least 3 months of consistent results with no need to adjust VKA dosing.26 Recall intervals for various clinical situations have not been extensively studied; rather, they evolved from

Optimal Therapeutic INR Range

The desired effect of VKA on the prothrombin time, expressed as INR, can be provided as a therapeutic range (eg, INR 2.0-3.0) or a therapeutic target (eg, INR 2.5). The former provides information on INR values considered acceptable for the patient, whereas the latter is intended to induce those managing anticoagulant therapy to strive for an ideal level.

In a systematic review of 19 studies (one RCT, five with analysis of INR-specific outcomes from RCTs, and 13 observational studies) reporting

VKA—Discontinuation of Therapy

There is a theoretical concern that abrupt VKA discontinuation may result in a temporary hypercoagulable state due to an imbalance in the rates of normalization of activity of the coagulation factors II, VII, IX, and X on the one hand and the natural inhibitors protein C and protein S on the other.143 Five small controlled trials (total n = 217) have addressed this issue.144, 145, 146, 147 The primary outcomes of four of the studies were laboratory results suggestive of a hypercoaguable state144

UFH—Dose Adjustment by Weight

Five RCTs compared initial IV UFH dosing according to a weight-based nomogram with a fixed-dose approach.149, 150, 151, 152, 153 The study by Jaff et al151 was excluded because no weight-adjusted group for the initial bolus was included. The study by Toth and Voll153 was excluded because the fixed dose varied by treating physician, and thromboembolic or bleeding complications were not specified. In the remaining three RCTs a total of 292 patients were randomized to either weight based or fixed

Should the Therapeutic Dose of LMWH Be Modified for Decreased Renal Function?

LMWH, as opposed to UFH, is primarily eliminated through renal excretion. We found no RCTs comparing a standard, body-weight-adjusted dose to a reduced dose of LMWH in severe renal insufficiency, defined as creatinine clearance < 30 mL/min.

A meta-analysis of 18 observational studies or subgroup analyses of studies using therapeutic doses of LMWH provides some indirect evidence on this patient population.157 On the basis of four of the studies, this review suggested that standard doses of LMWH

Fondaparinux Dose Management by Weight

Doses of heparins for the treatment of thrombosis often are administered according to patient body weight for both LMWH and UFH. Both total body weight and lean body weight have been used. In clinical trials, patients with morbid obesity (> 120-130 kg) often have been excluded. We did not identify any studies comparing weight-adjusted dosing of fondaparinux to standard doses not adjusted for weight. Two randomized trials for symptomatic venous thrombosis162, 163 used doses adjusted for the

Vitamin K for Patients Taking VKAs With High INRs Without Bleeding

The risk of bleeding increases significantly when the INR exceeds 4.5.165 In a retrospective review, patients with mechanical heart valves had a risk of adverse events that increased logarithmically from two per 100 patient-years at INR 2.5 to 4.9, to 4.8 per 100 patient-years for INR 5 to 5.5, then to 75 per 100 patient-years for INR ≥ 6.5.166 Similarly, a case-control analysis of adults sustaining intracerebral bleeding while on warfarin noted a doubling of intracerebral bleeding for every

Intensive Patient Education and Anticoagulation Outcomes

Intensive patient education (defined as dedicated patient education sessions beyond the usual VKA information distributed by pamphlet or the patient's usual provider) has been proposed to reduce adverse events related to anticoagulation and to improve TTR. Although better patient knowledge of anticoagulation has been associated with improved INR control, these were no randomized trials, and INRs were surrogate outcomes.208, 209

Seven RCTs (n = 1,195) compared supplemental patient education with

Acknowledgments

Author contributions: As Topic Editor, Dr Holbrook oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein

Dr Holbrook: served as Topic Editor.

Dr Schulman: served as Deputy Editor.

Dr Witt: served as a panelist.

Dr Vandvik:, served as a panelist.

Dr Fish: served as a frontline clinician.

Dr Kovacs: served as a panelist.

Dr Svensson: served as a panelist.

Dr Veenstra: served as a resource consultant.

Dr Crowther: served as a

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    Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

    Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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